(Adapted from Applicant's Abstract). The objective of the research proposed here is to develop potent and specific inhibitors of HIV-1 protease for use as effective agents in the treatment of AIDS. The design and synthesis of inhibitors can be divided into two parts. In the first, inhibitors of the active dimeric HIV-1 protease will be developed. By mapping the binding site of HIV-1 protease, the smallest effective inhibitor will be identified and modified to improve affinity. Studies in this section also include design of inhibitors modeled on the transition state of aspartyl protease-substrate complex. Inhibitors that incorporate (3S,4S) statine; (3S,4R) statine, or dipeptide isosteres in the inhibitor sequence will be synthesized and tested for inhibition against HIV-1 protease. In the second part, compounds that prevent dimerization of the inactive, monomeric units of HIV-1 protease or compounds that produce inactive dimers of the protease will be synthesized and tested for "anti- dimerization" activity. Molecular modeling will be extensively used in the design of such compounds. Synthesis of chromogenic substrates for HIV-1 protease is also proposed. If the proposed chromogenic compounds act as substrates for HIV-1 protease, a facilitated colorimetric assay for HIV-1 protease can be developed. Compounds which are found to be good inhibitors of HIV-1 protease will be tested in vitro to measure the potential drug's ability to inhibit the cytopathic effects of HIV-1.